Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions. METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437. FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts. INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac

Population density, water supply, and the risk of dengue fever in Vietnam: cohort study and spatial analysis.

BACKGROUND: Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. METHODS AND FINDINGS: We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks. CONCLUSIONS: Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary

Dynamics of multi-stage infections on networks

This paper investigates the dynamics of infectious diseases with a nonexponentially distributed infectious period. This is achieved by considering a multistage infection model on networks. Using pairwise approximation with a standard closure, a number of important characteristics of disease dynamics are derived analytically, including the final size of an epidemic and a threshold for epidemic outbreaks, and it is shown how these quantities depend on disease characteristics, as well as the number of disease stages. Stochastic simulations of dynamics on networks are performed and compared to output of pairwise models for several realistic examples of infectious diseases to illustrate the role played by the number of stages in the disease dynamics. These results show that a higher number of disease stages results in faster epidemic outbreaks with a higher peak prevalence and a larger final size of the epidemic. The agreement between the pairwise and simulation models is excellent in the cases we consider

Into the UV: The Atmosphere of the Hot Jupiter HAT-P-41b Revealed

For solar system objects, ultraviolet spectroscopy has been critical in identifying sources of stratospheric heating and measuring the abundances of a variety of hydrocarbon and sulfur-bearing species, produced via photochemical mechanisms, as well as oxygen and ozone. To date, fewer than 20 exoplanets have been probed in this critical wavelength range (0.2–0.4 μm). Here we use data from Hubble's newly implemented WFC3 UVIS G280 grism to probe the atmosphere of the hot Jupiter HAT-P-41b in the ultraviolet through optical in combination with observations at infrared wavelengths. We analyze and interpret HAT-P-41b's 0.2–5.0 μm transmission spectrum using a broad range of methodologies including multiple treatments of data systematics as well as comparisons with atmospheric forward, cloud microphysical, and multiple atmospheric retrieval models. Although some analysis and interpretation methods favor the presence of clouds or potentially a combination of Na, VO, AlO, and CrH to explain the ultraviolet through optical portions of HAT-P-41b's transmission spectrum, we find that the presence of a significant H− opacity provides the most robust explanation. We obtain a constraint for the abundance of H−, $\mathrm{log}({{\rm{H}}}^{-})=-8.65\pm 0.62$, in HAT-P-41b's atmosphere, which is several orders of magnitude larger than predictions from equilibrium chemistry for a ~1700–1950 K hot Jupiter. We show that a combination of photochemical and collisional processes on hot hydrogen-dominated exoplanets can readily supply the necessary amount of H− and suggest that such processes are at work in HAT-P-41b and the atmospheres of many other hot Jupiters

High tide or riptide on the cosmic shoreline? A water-rich atmosphere or stellar contamination for the warm super-Earth GJ 486b from JWST observations

Planets orbiting M-dwarf stars are prime targets in the search for rocky exoplanet atmospheres. The small size of M dwarfs renders their planets exceptional targets for transmission spectroscopy, facilitating atmospheric characterization. However, it remains unknown whether their host stars' highly variable extreme-UV radiation environments allow atmospheres to persist. With JWST, we have begun to determine whether or not the most favorable rocky worlds orbiting M dwarfs have detectable atmospheres. Here, we present a 2.8–5.2 μm JWST NIRSpec/G395H transmission spectrum of the warm (700 K, 40.3× Earth's insolation) super-Earth GJ 486b (1.3 R⊕ and 3.0 M⊕). The measured spectrum from our two transits of GJ 486b deviates from a flat line at 2.2σ − 3.3σ, based on three independent reductions. Through a combination of forward and retrieval models, we determine that GJ 486b either has a water-rich atmosphere (with the most stringent constraint on the retrieved water abundance of H2O > 10% to 2σ) or the transmission spectrum is contaminated by water present in cool unocculted starspots. We also find that the measured stellar spectrum is best fit by a stellar model with cool starspots and hot faculae. While both retrieval scenarios provide equal quality fits (${\chi }_{\nu }^{2}=1.0$) to our NIRSpec/G395H observations, shorter wavelength observations can break this degeneracy and reveal if GJ 486b sustains a water-rich atmosphere

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease

This work was supported by a research fellowship grant from the Crohn’s and Colitis in Childhood Research Association (CICRA) and a small project grant from Crohn’s and Colitis UK (CCUK). We would like to acknowledge Professor Ian Sanderson, who helped with the initial design of this work, and provided important support throughout. We would also like to thank Dr Gary Warne for his advice and assistance in the use of the sorting by flow cytometry. We would also like to thank Dr Raj Lahiri and Professor Graham Foster for the kind gift of the primers for the ISGs (2’5’ OAS and MxA)

Non-thermal emission processes in massive binaries

In this paper, I present a general discussion of several astrophysical processes likely to play a role in the production of non-thermal emission in massive stars, with emphasis on massive binaries. Even though the discussion will start in the radio domain where the non-thermal emission was first detected, the census of physical processes involved in the non-thermal emission from massive stars shows that many spectral domains are concerned, from the radio to the very high energies. First, the theoretical aspects of the non-thermal emission from early-type stars will be addressed. The main topics that will be discussed are respectively the physics of individual stellar winds and their interaction in binary systems, the acceleration of relativistic electrons, the magnetic field of massive stars, and finally the non-thermal emission processes relevant to the case of massive stars. Second, this general qualitative discussion will be followed by a more quantitative one, devoted to the most probable scenario where non-thermal radio emitters are massive binaries. I will show how several stellar, wind and orbital parameters can be combined in order to make some semi-quantitative predictions on the high-energy counterpart to the non-thermal emission detected in the radio domain. These theoretical considerations will be followed by a census of results obtained so far, and related to this topic... (see paper for full abstract)Comment: 47 pages, 5 postscript figures, accepted for publication in Astronomy and Astrophysics Review. Astronomy and Astrophysics Review, in pres

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Ten considerations for effectively managing the COVID-19 transition

Governments around the world have implemented measures to manage the transmission of coronavirus disease 2019 (COVID-19). While the majority of these measures are proving effective, they have a high social and economic cost, and response strategies are being adjusted. The World Health Organization (WHO) recommends that communities should have a voice, be informed and engaged, and participate in this transition phase. We propose ten considerations to support this principle: (1) implement a phased approach to a 'new normal'; (2) balance individual rights with the social good; (3) prioritise people at highest risk of negative consequences; (4) provide special support for healthcare workers and care staff; (5) build, strengthen and maintain trust; (6) enlist existing social norms and foster healthy new norms; (7) increase resilience and self-efficacy; (8) use clear and positive language; (9) anticipate and manage misinformation; and (10) engage with media outlets. The transition phase should also be informed by real-time data according to which governmental responses should be updated

Atmospheric retrieval of exoplanets

Exoplanetary atmospheric retrieval refers to the inference of atmospheric properties of an exoplanet given an observed spectrum. The atmospheric properties include the chemical compositions, temperature profiles, clouds/hazes, and energy circulation. These properties, in turn, can provide key insights into the atmospheric physicochemical processes of exoplanets as well as their formation mechanisms. Major advancements in atmospheric retrieval have been made in the last decade, thanks to a combination of state-of-the-art spectroscopic observations and advanced atmospheric modeling and statistical inference methods. These developments have already resulted in key constraints on the atmospheric H2O abundances, temperature profiles, and other properties for several exoplanets. Upcoming facilities such as the JWST will further advance this area. The present chapter is a pedagogical review of this exciting frontier of exoplanetary science. The principles of atmospheric retrievals of exoplanets are discussed in detail, including parametric models and statistical inference methods, along with a review of key results in the field. Some of the main challenges in retrievals with current observations are discussed along with new directions and the future landscape